Drug-releasing system of biodegradable polymer type

ABSTRACT

A method for producing compression-melt molded product using polylactic acid powder is described. The method comprises the steps of: 1) heat-melting polylactic acid having a weight-average molecular weight of 3,000-40,000 at 140-220° C., 2) allowing the melted polylactic acid to cool down to solidify at an ordinary or a lower temperature, 3) pulverizing the solidified polylactic acid at an ordinary temperature into powder, and 4) compressing the powder or a mixture powder prepared by addition of another ingredient, e.g., a biologically active compound, to the carrier powder in a mold at an ordinary temperature to cause the polylactic acid to melt into a molded product of a predetermined shape.

TECHNICAL FIELD

The present invention relates to a biodegradable polymer-based drugreleasing system, particularly to such a system utilizing a certainbiodegradable polymer for controlled release of drugs or agriculturalchemicals.

BACKGROUND ART

Systems for controlled release of biologically active compounds areknown, e.g., those which contain a biologically active compound in abase of suitable biodegradable polymers such as polylactic acid orpolyglycolic acid. For producing such systems, it is necessary to mix abiodegradable polymer with a biologically active compound, and then moldthe mixture thus prepared into certain shapes, e.g., a rod-like,plate-like or spherical shape, etc. appropriate for respective intendedways of use. The procedures for molding the mixture into those shapesgenerally include either heat-melting the mixture and pouring it into amold, followed by cooling and solidification, or dissolving the mixturein a solvent, pouring the solution into a mold, and then evaporating thesolvent. However, high temperatures are required for heat-melting, i.e.,140-175° C. for DL-polylactic acid or polylactic acid/polyglycolic acid,and 190-220° C. for D- or L-polylactic acid. Many of biologically activecompounds cannot withstand such high temperatures. Therefore, a methodthat includes a process of heat-melting of a mixture of a biologicallyactive compound with polylactic acid or polyglycolic acid is notsuitable as a general method for preparing a drug-releasing system.Also, in a method including a process of molding polylactic acid orpolylactic acid/polyglycolic acid after dissolving them in a solvent,complete removal of the solvent from the molded product becomesnecessary, which in general is very difficult, rendering such a methodunsuitable as a general method for preparing a drug-releasing system.

On the other hand, Japanese Patent Application Publication S61-172813describes a composite which is prepared by mechanically mixing abiologically active compound with DL-polylactic acid having a molecularweight of 1,000-5,000 or L- or D-polylactic acid having a molecularweight of 1,000, and heat-softening the mixture at 30-50° C. under thepressure of 200 kgf/cm² (=1.96×10³ N/cm²). Japanese Patent ApplicationPublication No. S62-207227 discloses a releasing system which isprepared by heat treatment of poly(DL-lactic acid) (Mn=15,000) at 40° C.for 10 seconds under the pressure of 50 kgf/cm² (=4.9×10² N/cm²).

However, in the method for preparing the systems described in thesepublications, it is typically DL-polylactic acid that is shown to bemoldable without heating, according to what is described in theexamples. Examples employing one of the optical isomers, D- orL-polylactic acid, alone are disclosed but they are limited to thosehaving a very small molecular weight (1,000). As aforementioned, themelting point of polylactic acid differs depending on whether thepolylactic acid is DL-, D- or L-form, among which also the softeningtemperatures naturally differ. The melting and softening points varydepending on the molecular weight; the greater the molecular weight, themore difficult it becomes to soften and melt. For example, a studyperformed by the present inventors using powder directly prepared bypulverizing L-polylactic acid having a weight-average molecular weightof over 3,000, its compression under room temperature caused no fusionof the particles, failing to give a molded product.

Upon this background, the objective of the present invention is toprovide a method for production of a drug-releasing system containingpolylactic acid and a biologically active compound, wherein the methodrequires neither heating nor solvent in the molding of the mixture ofthe biologically active compound and polylactic acid.

DISCLOSURE OF INVENTION

The present inventors found that the powder obtained through a processin which polylactic acid was once heat-melted at a temperature in apredetermined range, then cooled down to solidify at an ordinary or alower temperature, and pulverized at an ordinary temperature behavesdifferently under pressure from powder that was obtained by directlypulverizing polylactic acid that had not been subjected to aheat-melting process at a predetermined temperature. More specifically,while powder prepared by simple pulverization of L-polylactic acid couldnot be molded under pressure at an ordinary temperature, thusmaintaining the powder form, powder prepared by pulverizing polylacticacid that had once been heat-melted and cooled down to solidify at anordinary or a lower temperature, allows easy fusion of polylactic acidparticles, thus, under mild pressure, giving a transparent moldedproduct through easy melting and unification of the polylactic acidpowder. Also found was that a mixture prepared by mixing such powderfrom heat-melted polylactic acid with other ingredients, e.g., abiologically active compound, allows melting and unification ofpolylactic acid under mild pressure, thus giving a molded productcontaining a dispersed biologically active compound. It was furtherfound that a molded product prepared in such a manner releases abiologically active compound continuously almost without an initialburst, and at a substantially constant (zero-order) rate, as opposed toa two-phased release observed with a molded product prepared by aconventional method of compression with heating. The present inventionwas accomplished through further studies about various applicationsbased on these findings.

Thus, the present invention provides a method for production of apolylactic acid-based compression-melt molded product comprising thesteps of:

1) heat-melting polylactic acid having a weight-average molecular weightof 3,000-40,000 at 140-220° C.,

2) allowing the melted polylactic acid to cool down to solidify at anordinary or a lower temperature,

3) pulverizing the solidified polylactic acid at an ordinary temperatureinto powder, and

4) compressing the powder, or a mixture powder prepared by addition ofanother ingredient to the carrier powder, in a mold at an ordinarytemperature to cause the polylactic acid to melt into a molded productof a predetermined shape.

The method for production may further comprise a step of producing oneor more smaller-sized molded products by cutting a length of moldedproduct prepared by the above-defined steps into shorter parts.

The present invention further provides a method for production of abiodegradable polymer-based drug releasing system comprising the stepsof:

1) heat-melting polylactic acid having a weight-average molecular weightof 3,000-40,000 at 140-220° C.,

2) allowing the melted polylactic acid to cool down to solidify at anordinary or a lower temperature,

3) pulverizing the solidified polylactic acid at an ordinary temperatureinto powder, and

4) mixing the powder with a powder of a biologically active compound andcompressing thus prepared mixture powder in a mold at an ordinarytemperature to cause the polylactic acid to melt into a molded productof a predetermined shape.

The method for production may further comprise a step of producing oneor more smaller-sized drug-releasing systems by cutting a length ofmolded system prepared by the above-defined steps into shorter parts.

Any of DL-, D- and L-polylactic acid may be employed in the presentinvention. In the present invention, the range of molecular weight inwhich particularly notable improvement of fusion of the polylactic acidparticles is achieved is 8,000-30,000 for DL-polylactic acid and3,000-30,000 for D- and L-polylactic acid.

In the present invention, the process of compression may be conductedunder such pressure that will cause the polylactic acid powder to meltand unite in several to several dozen seconds.

In the present invention, in order to ensure pressure-driven melting andunification of polylactic acid to take place in the mixture ofpolylactic acid and another ingredient or a biologically activecompound, the weight ratio of such another ingredient or a biologicallyactive compound to polylactic acid is usually not more than 2/5,preferably not more than 3/10, and particularly preferably not more than1/9. Insofar as these ranges of weight ratio are met, the amount of suchanother ingredient or a biologically active compound may be determinedaccording to the purpose of the product.

A mold used for the molding preferably has a cylindrical inner surface,and compression of a mixture powder consisting of polylactic acid and abiologically active compound preferably takes place in the direction ofthe axis of the mold. The cylindrical inner surface, which is notnecessarily one having a circular cross section, may have an elliptic orpolygonal cross section.

The present invention further provides a method for production of abiodegradable polymer-based drug releasing system comprising the stepsof:

1) heat-melting polylactic acid having a weight-average molecular weightof 3,000-40,000 at 140-220° C.,

2) allowing the melted polylactic acid to cool down to solidify at anordinary or a lower temperature,

3) pulverizing the solidified polylactic acid at an ordinary temperatureinto powder, and

4) compressing, at an ordinary temperature, the powder or a mixturepowder prepared by mixing the powder with a powder of a biologicallyactive compound in an amount giving a weight ratio of the latter powderto the former of not more than 2/5, preferably not more than 3/10, orparticularly preferably not more than 1/9, in a mold which is removablyprovided with a column-like core cylinder placed along the axis of themold, to form a molded product defining a column-like hollow region,

5) removing the core cylinder and either pouring into the hollow regiona mixture powder prepared by mixing powder produced through a process inwhich polylactic acid having a weight-average molecular weight of3,000-40,000 is heat-melted at 140-220° C., then cooled down to solidifyat an ordinary or a lower temperature and pulverized at an ordinarytemperature, and powder of a biologically active compound in an amountgiving a weight ratio of the latter powder to the former of not morethan 2/5, preferably not more than 3/10, or particularly preferably notmore than 1/9, or inserting into the hollow region a molded productproduced by compressing the mixture powder at an ordinary temperature,and

6) compressing the mixture powder, or the molded product therefrom, inthe hollow region at an ordinary temperature to cause the polylacticacid in the mixture powder to melt and the mixture powder to be moldedappressed against the inner wall of the hollow region, thereby obtaininga united molded product.

The step of pouring into the hollow region a mixture prepared by mixingpolylactic acid and a biologically active compound, or of inserting intothe hollow region a molded product produced by compressing the mixturepowder at an ordinary temperature, may be conducted by any method asdesired, such as the method described in Yakuzaigaku, Vol.49(No.2):p.116-126(1989) or other publicly known methods or methods basedon them.

According to the above method, a biodegradable polymer-based drugreleasing system is obtained in which the core consisting of a moldedmixture of a drug and polylactic acid is surrounded by an molded outershell consisting of polylactic acid alone or of a mixture of polylacticacid and a biologically active compound. The method for production mayfurther comprise a process of producing smaller-sized drug-releasingsystems by cutting a length of molded system produced by theabove-defined steps into shorter parts. In the method for production,when the outer shell contains a biologically active compound, the weightratio of the biologically active compound to polylactic acid in eitherthe outer shell or the core may be chosen within the above-mentionedranges, in accordance with the an intended releasing pattern. The coreand the outer shell may contain the same biologically active compound ordifferent ones.

The present invention further provides a method for production of theaforementioned biodegradable polymer-based drug releasing systemconsisting of a core and an outer shell, the method further comprisingthe steps of:

1) pouring in the mold onto the end face of the molded product with theexposed hollow region produced by the steps 1-6 above, powder producedby a process in which polylactic acid having a weight-average molecularweight of 3,000-40,000 is heat-melted at 140-220° C., then cooled downto solidify at an ordinary or a lower temperature and pulverized at anordinary temperature or a mixture powder prepared by mixing said powderand powder of a biologically active compound in an amount giving aweight ratio of the latter powder to the former of not more than 2/5,preferably not more than 3/10, or particularly preferably not more than1/9, and

2) compressing said powder or the mixture powder in the direction of theaxis of the mold at an ordinary temperature to cause the polylactic acidto melt, thereby molding the polylactic acid powder or the mixturepowder, thus giving one united molded product together with the moldedproduct produced by the steps 1-6.

According to the method for production, a biodegradable polymer-baseddrug releasing system is obtained which has also an outer shell coveringthe exposed hollow region, whose interior has been completely orpartially filled with a molded product consisting of a mixture ofpolylactic acid and a biologically active compound. In the method forproduction, where covering the exposed hollow region with a mixture ofpolylactic acid and a biologically active compound, the weight ratio ofthe biologically active compound to polylactic acid in the mixture isusually not more than 2/5, preferably not more than 3/10, andparticularly preferably not more than 1/9. The weight ratio may beadjusted to the weight ratio of the biologically active compoundcontained in the already formed outer shell, though such an adjustmentis not necessary. The core and the outer shell may contain the same ordifferent biologically active compounds.

The present invention further provides a method for production of abiodegradable polymer-based drug-releasing system comprising the stepsof:

1) heat-melting polylactic acid having a weight-average molecular weightof 3,000-40,000 at 140-220° C.,

2) allowing the melted polylactic acid to cool down to solidify at anordinary or a lower temperature,

3) pulverizing the solidified polylactic acid at an ordinary temperatureinto powder, and

4) compressing, at an ordinary temperature, the powder or a mixturepowder prepared by mixing the powder with a powder of a biologicallyactive compound in an amount giving a weight ratio of the latter powderto the former of not more than 2/5, preferably not more than 3/10, orparticularly preferably not more than 1/9, in a mold which is removablyprovided with a column-like core cylinder placed along the axis of themold to form a molded product defining a column-like hollow region,

5) removing the core cylinder and pouring into the hollow region abiologically active compound or a composition containing the same,

6) pouring onto the end face of the molded product with the exposedhollow region, powder produced by a process in which polylactic acidhaving a weight-average molecular weight of 3,000-40,000 is heat-meltedat 140-220° C., then cooled down to solidify at an ordinary or a lowertemperature and pulverized at an ordinary temperature or a mixturepowder prepared by mixing said powder and powder of a biologicallyactive compound in an amount giving a weight ratio of the latter powderto the former of not more than 2/5, preferably not more than 3/10, orparticularly preferably not more than 1/9, and

7) compressing said powder or the mixture powder in the direction of theaxis of the mold at an ordinary temperature to cause the polylactic acidto melt, thereby molding the polylactic acid powder or the mixturepowder, thus giving one united molded product containing in thehermetically sealed hollow region a biologically active compound or acomposition thereof.

According to the method for production, a biodegradable polymer-baseddrug releasing system is obtained in which a biologically activecompound or a composition thereof is covered by an outer shell made ofpolylactic acid or a mixture consisting of polylactic acid and abiologically active compound. The biodegradable polymer-based drugreleasing system obtained according to the production method can containin its interior a biologically active compound in its pure form or athigh concentrations. The biologically active compound contained in theouter shell may be the same as or different from the biologically activecompound contained in the interior.

Also in the production of the aforementioned biodegradable polymer-baseddrug releasing system having a structure consisting of an outer shelland a core, any of DL-, D- and L-polylactic acid may be used. In themethod for production, the molecular weight range within which mostremarkable benefit is obtained is 8,000-30,000 for DL-polylactic acidand 3,000-30,000 for D- or L-polylactic acid.

Also in the production of the aforementioned biodegradable polymer-baseddrug releasing system consisting of an outer shell and a core, acompression process may be usually conducted under such a pressure thatcauses polylactic acid powder to melt and become united.

Any compound may be employed as desired as another ingredient or abiologically active compound in the aforementioned compression-meltmolded product from polylactic acid or in any of the aforementionedbiodegradable polymer-based drug-releasing systems. Examples of suchcompounds included, but are not limited to, antibiotics, antimicrobials,antivirals, vascularization suppressors, anti-glaucoma agents,anti-cataract agents, anticancer agents, vaccine antigens andphysiologically active peptides.

The present invention also provides compression-melt molded productsfrom polylactic acid or biodegradable polymer-based drug-releasingsystems of that are produced by any of the aforementioned productionmethods. Such systems may be implanted in various parts of the bodyaccording to the purpose of application, e.g., beneath the skin, in theeyeball, in the brain, or the like.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph illustrating the amount of indomethacin released overtime from the drug-releasing systems of Example 5 and Examples forComparison 1 and 2.

FIG. 2 is a graph illustrating the amount of indomethacin released overtime from the drug-releasing systems of Example 5 and Examples forComparison 1 and 2 implanted at the center of the vitreous body ofrabbits.

BEST MODE FOR CARRYING OUT THE INVENTION

In the present invention, the term an “ordinary temperature” means atemperature of 20-30° C. A temperature lower than this is meant by theterm a “lower temperature”.

A biologically active compound and polylactic acid power are mixed at anordinary temperature. However, if a biologically active compound is aliquid at an ordinary temperature, they may be mixed at a lowertemperature in order to allow the compound to solidify during the mixingprocess.

The present invention has enabled complete melting and unification ofpolylactic acid particles under a small pressure as a result ofproviding the steps of heat-melting and cooling down for solidificationof polylactic acid before pulverization and then conductingpulverization of polylactic acid at an ordinary temperature, not a lowertemperature. Thus, as the present invention does not require any heatingduring molding, it is suitable for the production of a biodegradablepolymer-based drug releasing system employing a biologically activecompound that is sensitive to heat. Also, as only a small pressure isrequired to cause polylactic acid particles to melt in the presentinvention, it is also suitable when employing a biologically activecompound that is sensitive to pressure. Further, as the presentinvention needs no solvent in molding polylactic acid, it has advantagesthat no solvent removal process is required, and that a safer product isobtained than by a method for production utilizing a solvent.

Among the biodegradable polymer-based drug-releasing systems producedaccording to the present invention, those of the simplest structure canbe used to release a biologically active compound continuously and at anearly constant rate for a prolonged time.

Among the biodegradable polymer-based drug releasing system producedaccording to the present invention, those consisting of a core and anouter shell can be used to release a biologically active compound indifferent releasing patterns through proper setting of the relativedimensions of the core and the outer shell as well as the weight ratioof the biologically effective compound contained in the core and theouter shell, and also in accordance with whether the end face of thecore is exposed or it is covered with a shell consisting of, orcomprising, polylactic acid. For example, systems which have an outershell made of neat polylactic acid and whose exposed core in the endface is also covered with the shell can be used to continuously releasea biologically active compound at a constant rate only after the lapseof certain length of time during which no release of the biologicallyactive compound takes place, rendering them to be useful for medicalapplications such as vaccine inoculation, or in the field of agriculture(e.g. for poultry plants), and the like. Using a system containing abiologically active compound also in the outer shell, it is possible torealize release of a biologically active compound at one constant rateuntil the lapse of a certain period of time and then, after the lapse ofthe period, at another constant rate. Furthermore, by employing amultilayered core/outer shell, the present invention can readily providea system that releases a biologically active compound in a pulsedpattern. For providing a multilayered core/outer shell, the step of coreformation, for example but without limitation, may include a furtherstep, in which a second, narrower core cylinder is employed to define anarrower hollow region in the core, and a mixture of polylactic acid anda biologically active compound is compressed in the hollow region tomelt and become united.

If different biologically active compounds are used in the outer shelland the core, respectively, a biodegradable polymer-based drug releasingsystem will be obtained which continuously releases the drug containedin the shell at a constant rate until the lapse of a predeterminedperiod of time, and then, after the lapse of the period, continuouslyreleases the drug contained in the core at a constant rate. Also, in thecase of a biodegradable polymer-based drug releasing system in which thecore is exposed in the end face of the system, addition of differentbiologically active compound in the shell and the core, respectively,gives a drug-releasing system which continuously releases the bothbiologically active compounds at the same time and at constant rates,avoiding direct contact of the both compounds. This method is useful,particularly where, e.g., the both biologically active compounds arechemically destabilized by their direct contact.

Furthermore, a biodegradable polymer-based drug releasing system can beprovided in which a biologically active compound or a compositionthereof is encapsulated in a shell consisting of polylactic acid or amixture of polylactic acid and a biologically active compound, in orderto release a biologically active compound at a burst only after thelapse of a certain period of time during which the biologically activecompound is not released. Using a system of this type, the content of abiologically active compound can be increased without difficulty, as thesuch a system can contain a pure biologically active compound or acomposition containing a high concentration of the compound.

In the present invention, a compression-melt molded product or abiodegradable polymer-based drug releasing system may be provided in anyof a variety of shapes as desired, e.g., a rod-like, plate-like,spherical shapes, etc. in accordance with the purpose of use, and theshape and structure of a mold may be determined in conformity to theintended shape of a product. In addition, by defining a through-bore oran indentation in a rod-shaped or spherical system, etc., a system ofthe present invention may be provided that can be attached to anothersupport body such as a supporting element of intraocular lens.

The present invention will be described in further detail with referenceto Examples. However, it is not intended that the present invention berestricted to the Examples.

Example 1

L-polylactic acid having a weight-average molecular weight of 5,000 washeated to melt at 150° C., then allowed to cool down to solidify, andpulverized in a mortar at an ordinary temperature. The powder ofpulverized L-polylactic acid was poured into a Teflon tube of approx.1-mm inside diameter. Stainless steel rods of approx. 1-mm diameter wereinserted from both end of the tube and the L-polylactic acid was gentlypressed for several to several dozen seconds at room temperature. Thiscause the powder of polylactic acid to melt and become united into atransparent rod of L-polylactic acid (1 mm in diameter, 3 mm in length).

Example 2

A Teflon rod of 1-mm diameter and 2 cm in length was inserted into aTeflon tube of 2-mm inside diameter along the central axis thereof. Theboth end of the Teflon tube were plugged with spacer tubes (of Teflon)of 1-mm inside diameter and 2-mm outside diameter, with the Teflon rodprotruding from both ends of the Teflon tube inserted in the spacertubes, thereby enabling to secure the Teflon rod along the central axisof the Teflon tube of 2-mm inside diameter. One of the spacers wasremoved, the same polylactic acid powder as used in Example 1 was pouredinto the space defined by the Teflon tube and the Teflon rod, and thespacer that had been removed was attached again. The polylactic acidpowder was gently pressed from both ends using the spacers placed onboth ends for several to several dozen seconds at room temperature tocause polylactic acid powder to melt and become united, thereby forminga transparent molded product of L-polylactic acid having a passingthrough hollow region. Only the Teflon rod used as a core cylinder wasthen removed, a mixture powder consisting of the polylactic acid powderused in Example 1 and indomethacin (polylactic acid:indomethacin=9:1 (byweight)) was poured into the hollow region of the molded product ofpolylactic acid, and gently pressed from both ends using stainless steelrods of 1-mm diameter for several to several dozen seconds at roomtemperature, causing the mixture powder to solidify. The productcomprising a core, which consists of polylactic acid and the drug, andsurrounding polylactic acid was removed and cut into 3 mm in length.

Example 3

A molded produced of 2-mm outer diameter and 3 mm in length prepared inExample 2 was inserted into a Teflon tube of 2-mm inside diameter. Onboth ends of the molded product was poured the same polylactic acidpowder as used in Example 1, and the powder was gently pressed withstainless steel rods of 2-mm diameter for several to several dozenseconds at room temperature to cause the polylactic acid powder to meltand become united, giving a molded product.

Example 4

A Teflon rod of 1-mm diameter and 2 cm in length was inserted into aTeflon tube of 2-mm inside diameter along the central axis thereof. Theboth end of the Teflon tube were plugged with spacer tubes (of Teflon)of 1-mm inside diameter and 2-mm outside diameter, with the Teflon rodprotruding from both ends of the Teflon tube inserted in the spacertubes, thereby securing the Teflon rod along the central axis of theTeflon tube of 2-mm inside diameter. One of the spacers was removed, thesame polylactic acid powder as used in Example 1 was poured into thespace defined by the Teflon tube and the Teflon rod, and the spacer thathad been removed was attached again. The polylactic acid powder wasgently pressed using the spacers for several to several dozen seconds atroom temperature to cause polylactic acid powder to melt and becomeunited, thereby forming a transparent molded product of L-polylacticacid having a passing through hollow region. Only the Teflon rod used asa core cylinder was then removed. Indomethacin powder was poured intothe hollow region of the molded product of polylactic acid, and the samepolylactic acid powder as used in Example 1 then was poured on both endsof the molded product and gently pressed with stainless steel rods of2-mm diameter for several to several dozen seconds at room temperatureto cause the polylactic acid powder to melt, thereby giving a unitedmolded product encasing indomethacin in the hollow region thereof.

Example 5

Nine hundred mg of L-polylactic acid having a weight-average molecularweight of 5,000 was heated to melt at 180° C., then allowed to cool downfor one minute to solidify, and pulverized in a mortar for five minutesat an ordinary temperature. The polylactic acid powder thus obtained wasmixed with indomethacin at a weight ratio of 9:1. The mixture powder waspoured into a Teflon tube of approx. 1-mm inside diameter up to a heightof approx. 1 cm. Stainless steel rods of approx. 1-mm diameter wereinserted from both ends of the tube and the polylactic acid powder wasgently pressed for several to several dozen seconds at an ordinarytemperature to cause the polylactic acid powder to melt and integrateinto a polylactic acid rod (1 mm in diameter, 3 mm in length) containingindomethacin. The rod was placed in five ml of phosphate buffer (pH 7),and stirred by shaking for 36 days at 37° C. at 180 cpm. During thestirring period, the whole volume of the fluid was exchanged over time,and indomethacin concentration in the solution determined by HPLC tocalculate the amount of indomethacin released into the solution. Theresults are shown in FIG. 1 as the cumulative amount of releasedindomethacin. As apparent from FIG. 1, it is noted that indomethacin wasreleased at a substantially constant rate (zero-order), substantiallywithout an initial burst, for 20 days up to its almost complete release.

Example 6

Nine hundred mg of L-polylactic acid having a weight-average molecularweight of 5,000 was heated to melt at 180° C., then allowed to cool downfor one minute to solidify, and pulverized in a mortar for five minutesat an ordinary temperature. The polylactic acid powder thus obtained wasmixed with indomethacin at a weight ratio of 10:3. The mixture powderwas poured into a Teflon tube of approx. 1-mm inside diameter up to aheight of approx. 1 cm. Stainless steel rods of approx. 1-mm diameterwere inserted from both ends of the tube and the polylactic acid powderwas gently pressed for several to several dozen seconds at an ordinarytemperature to cause the polylactic acid powder to melt and integrateinto a polylactic acid rod (1 mm in diameter, 3 mm in length) containingindomethacin.

Example 7

Nine hundred mg of L-polylactic acid having a weight-average molecularweight of 5,000 was heated to melt at 180° C., then allowed to cool downfor one minute to solidify, and pulverized in a mortar for five minutesat an ordinary temperature. The polylactic acid powder thus obtained wasmixed with indomethacin at a weight ratio of 5:2. The mixture powder waspoured into a Teflon tube of approx. 1-mm inside diameter up to a heightof approx. 1 cm. Stainless steel rods of approx. 1-mm diameter wereinserted from both ends of the tube and the polylactic acid powder wasgently pressed for several to several dozen seconds at an ordinarytemperature to cause the polylactic acid powder to melt and becomeunited into a polylactic acid rod (1 mm in diameter, 3 mm in length)containing indomethacin.

Example for Comparison 1

Nine hundred mg of L-polylactic acid having a weight-average molecularweight of 5,000 was pulverized in a mortar for five minutes at anordinary temperature. The polylactic acid powder thus obtained was mixedwith indomethacin at a weight ratio of 9:1, transferred into a petridish and completely melted at 170-180° C. After cooling down andsolidification, the mixture was pulverized in a mortar for five minutesat an ordinary temperature. The mixture powder was poured into a Teflontube of approx. 1-mm inside diameter up to a height of approx. 1 cm.Stainless steel rods of approx. 1-mm diameter were inserted from bothends of the tube and the mixture powder was compression molded at anordinary temperature to form a polylactic acid rod (1 mm in diameter, 3mm in length) containing indomethacin. The rod was placed in five ml ofphosphate buffer (pH 7), and stirred by shaking for 36 days at 37° C. at180 cpm. During the stirring period, the whole volume of the fluid wasexchanged over time, and indomethacin concentration in the solutiondetermined by HPLC to calculate the amount of indomethacin released intothe solution. The results are shown in FIG. 1 as the cumulative amountof released indomethacin. As apparent from FIG. 1, it is noted that therelease of indomethacin from this rod of this Example for Comparisonexhibits an initial burst.

Example for Comparison 2

Nine hundred mg of L-polylactic acid having an average molecular weightof 5,000 was pulverized in a mortar for five minutes at an ordinarytemperature. The polylactic acid powder thus obtained was mixed withindomethacin at a weight ratio of 9:1, and poured into a Teflon tube upto a height of approx. 1 cm. Stainless steel rods of approx. 1-mmdiameter were inserted from both end of the tube and compression-moldingwas conducted while heat-softening at 80-100° C. to form a polylacticacid rod (1 mm in diameter, 3 mm in length) containing indomethacin. Therod was placed in five ml of phosphate buffer (pH 7), and stirred byshaking for 25 days at 37° C. at 180 cpm. During the stirring period,the whole volume of the fluid was exchanged over time, and indomethacinconcentration in the solution determined by HPLC to calculate the amountof indomethacin released into the solution. The results are shown inFIG. 1 as the cumulative amount of released indomethacin. As apparentfrom FIG. 1, it is noted that the release of indomethacin from this rodof this Example for Comparison exhibited a typical two-phased patternhaving bursts at initial and late stages.

Example of Implantation Test Releasing Characteristics of IntraocularBiodegradable Implantable Polymer Rod in Rabbit's Vitreous Humor

Test Preparation: The indomethacin-containing polylactic acid rods ofExample 5 and Examples for Comparison 1 and 2 were used.

Test Animals: Japanese albino rabbits (body weight of 1.8-2 kg), devidedinto three groups, were used.

Test procedure: The rabbits were given general anesthesia, and a testpreparation was implanted at the center of the vitreous body, using aneedle for syringe of 1-mm inside diameter, through the sclera at a sitethree mm away from the limbus. The rabbits were sequentially sacrificed1, 3, 7, 14, 21, 28 and 35 days after implantation, and the eyes wereremoved and frozen at −80° C. The implanted preparation was separatedand the content of the drug in the preparation was determined by HPLC.

Results: The results are shown by a graph in FIG. 2. The content ofindomethacin in the preparation of Example 5 was found to graduallydecrease over about 20 days until most of the drug was lost, indicatingthat the drug was constantly released from the preparation during theperiod. On the other hand, in the preparation of Example for Comparison2, the content of indomethacin quickly decreased following implantationof the preparation, but remained substantially unchanged during thefollowing period of from one through three days, and then started todecrease again. Thus, it is seen that release of indomethacin from thepreparation of Example for Comparison 2 exhibited the typical 2-phasedreleasing pattern, i.e., a quick release immediately after implantation,a halt thereafter, followed by resumption of release. As for thepreparation of Example for Comparison 1, all the indomethacin wassubstantially released 14 days after implantation, apparently indicatinga quicker release than that of the preparation of Example 5. Thesefindings indicate that the initial burst found in the release test inthe phosphate buffer is also likely to take place with the preparationsof the Examples for Comparison when they are implanted in the vitreous.

INDUSTRIAL APPLICABILITY

The present invention is particularly suited for production of abiologically degradable polymer-based drug-releasing system employing abiologically active compound that is sensitive to heat or pressure, forthe present invention enables to easily and completely melt and unitepolylactic acid particles by applying small pressure, thereby totallyeliminating the necessity of heating during molding. Also, as no solventis employed in the molding of polylactic acid, the present inventioneliminates concern about remaining solvent in the final product.

1. A method for production of a biodegradable polymer-based drugreleasing system consisting of the steps of: 1) heat-melting polylacticacid having a weight-average molecular weight of 3,000-40,000 at140-220° C., 2) allowing the melted polylactic acid prepared in step (1)to cool down to solidify at a temperature of about 20° C. to 30° C., 3)pulverizing the solidified polylactic acid prepared in step (2) intopowder at about 20° C. to 30° C., and 4) mixing the powder prepared instep (3) with a powder of a biologically active compound at about 20° C.to 30° C. and compressing thus prepared mixture powder in a mold atabout 20° C. to 30° C. to cause the polylactic acid to melt into amolded product of a predetermined shape.
 2. The method of claim 1,wherein the polylactic acid is DL-polylactic acid, D-polylactic acid orL-polylactic acid.
 3. The method of claim 1, wherein the polylactic acidis DL-polylactic acid and the weight-average molecular weight of thepolylactic acid is 8,000-30,000.
 4. The method of claim 1, wherein thepolylactic acid is D-polylactic acid or L-polylactic acid and theweight-average molecular weight of the polylactic acid is 3,000-30,000.5. The method of claim 1, wherein the weight ratio of the biologicallyactive compound to polylactic acid is not more than 2:5 in the mixturepowder.
 6. The method of claim 1, wherein the mold has a cylindricalinner surface and the mixture powder is compressed in the direction ofthe axis of the mold.
 7. The method of claim 1, wherein the biologicallyactive compound is selected from the group consisting of antibiotics,antimicrobials, antivirals, vascularization suppressors, anti-glaucomaagents, anti-cataract agents, anticancer agents and vaccine antigens. 8.The method of claim 1, wherein the biologically active compound is aphysiologically active peptide.